Angiogenesis is critical during development and pregnancy, for wound healing, and for revascularization of ischemic tissues and tumorigenesis. Chemotactic cytokines (or chemokines), which signal via G protein- coupled receptors (GPCRs), regulate angiogenesis but have not been studied as intensively as other angiogenic factors and the receptor that mediates chemokine regulation of angiogenesis is not known. Based on he findings that GPCRs may form heterodimers for effective signaling, I hypothesize that the GPCR that mediates the angiogenic effects of CXC chemokines (Ang-GPCR), is a heterodimer of CXCR4, the GPCR for stromal-derived factor-1 (SDF-1), and DARC, the Duffy antigen-receptor for chemokines that has not been shown to signal but that binds CXC chemokines.
The Specific Aims that I will pursue are: #1 To show that functional Ang-GPCRs are expressed on endothelial cells under appropriate conditions and determine the cellular responses mediated by Ang-GPCR. #2 To co-express DARC and CXCR4 and demonstrate that a receptor that exhibits the signaling characteristics of Ang-GPCR is formed. #3 To show that Ang-GPCR is a heterodimer of DARC and CXCR4. #4 To show that stromal cell-derived factor-1 (SDF-1), which is an agonist at CXCR4, and the KC gene product (KC), which is the mouse homolog of growth-related oncogene alpha (GROalpha) that binds to DARC, are co-stimulatory ligands for Ang-GPCR in mice. Because GPCRs are excellent drug targets, I suggest if I show that the heterodimer of DARC and CXCR4 is Ang-GPCR that this receptor would be an excellent target for angiogenic therapy.
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